DESCRIPTION (provided by principal investigator): The restless legs syndrome (RLS) is a common movement disorder, characterized by an almost irresistible urge to move the legs. According to recent estimates, it affects 5-20 percent of adults and often has a substantial impact on sleep, daily activities and quality of life. However, the etiology of RLS remains unknown. Large, well-characterized cohort studies with validated assessment of lifestyle factors could provide critical information and lead to new approaches for prevention and treatment. Particularly, there is a need of further large prospective studies on the clinical impact of RLS given a high prevalence of the syndrome. Because the majority of RLS patients (~90 percent) remain undiagnosed, studies based on clinical series may not adequately represent the spectrum and natural history of the disease. Some studies, primarily cross-sectional, found that RLS patients had a higher prevalence of a number of chronic diseases (e.g., cardiovascular disease and Parkinson's disease), and an increased risk of mortality. We propose here to document the occurrence of RLS among female and male participants of two large and well established cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses'Health Study II (NHS II), for the purpose of addressing several important hypotheses related to the etiology and clinical impacts of RLS. The HPFS and NHS II were initiated in 1986 and 1989 respectively, including 51,529 male health professionals (aged 45-70 in 1986) and 116,678 middle-aged female registered nurses (aged 25-42 in 1989). Information of RLS, using standardized questions, has been collected since 2002 in the HPFS and 2005 in the NHS II. We will investigate 1) whether blood donation, obesity, genetic components are associated with RLS risk during 4-6 years of follow-up;and 2) whether RLS is associated with an increased risk of chronic diseases (coronary heart disease, stroke, hypertension, Parkinson's disease and erectile dysfunction) and mortality in the HPFS (2002-2010) and the NHS II (2005-2011). We expect to be able to document 5167 prevalent and 935 incident RLS cases, which will provide unprecedented power to test the proposed hypotheses. In addition, documentation of the occurrence of RLS in our cohorts is the critical component of a large bank of information that includes multiple and validated assessments of several aspects of lifestyle, including diet and health habits, over a period of 16 years in men and women, and prospectively collected blood and DNA samples. This bank of information is unique and will be of significance for future investigations on RLS and biomarkers and genetic characteristics. PUBLIC HEALTH RELEVANCE: The primary aim of this application is to examine whether blood donation, obesity and genetic components influence risk of restless legs syndrome and whether restless legs syndrome increases risk of chronic diseases and mortality.